Polymorphisms of the DNA Methyltransferase 1 Associated with Reduced Risks of Helicobacter pylori Infection and Increased Risks of Gastric Atrophy

Abstract

IntroductionDNA methyltransferase-1(DNMT1) is an important enzyme in determining genomic methylation patterns in mammalian cells. We investigated the associations between SNPs in the DNMT1 gene and risks of developing H. pylori seropositivity, gastric atrophy and gastric cancer in the Chinese population.MethodsThe study consisted of 447 patients with gastric cancer; 111 patients with gastric atrophy; and 961 healthy controls. Five SNPs, rs10420321, rs16999593, rs8101866, rs8111085 and rs2288349 of the DNMT1 gene were genotyped. Anti-H.pylori IgG was detected by ELISA. Gastric atrophy was screened by the level of serum pepsinogen Ιand II and then confirmed by endoscopy and histopatholgical examinations.ResultsThe age- and sex-adjusted OR of H. pylori seropositivity was 0.67 (95%CI: 0.51–0.87) for rs8111085 TC/CC genotypes, significantly lower than the TT genotype in healthy controls. The adjusted OR of H.pylori seropositivity was 0.68 (95%CI: 0.52–0.89) for rs10420321 AG/GG genotypes. In addition, patients carrying rs2228349 AA genotype have a significantly increased risk for H.pylori seropositivity (OR = 1.67; 95%CI: 1.02–2.75). Further haplotype analyses also showed that the ATTTG and ATCTA are significantly associated with increased risks in H.pylori infection compared to the GTCCG haplotype (OR = 1.38, 95%CI: 1.08–1.77; OR = 1.40, 95% CI: 1.09–1.80). The adjusted ORs of gastric atrophy were 1.66 (95%CI: 1.06–2.61) for rs10420321 GG genotype, and 1.67 (95%CI 1.06–2.63, P = 0.03) for rs8111085 CC genotype, but no association was found between SNPs in the DNMT1 gene and risk of developing gastric cancer.ConclusionsIndividuals with rs10420321 GG and rs8111085 CC genotype of the DNMT1 gene were associated with reduced risks for H.pylori infection. On the other hand, higher risks of gastric atrophy were found in the carriers with these two genotypes compared to other genotypes. Our results suggested that SNPs of DNMT1 could be used as genotypic markers for predicting genetic susceptibilities to H.pylori infection and risks in gastric atrophy.

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

“…In our previous study among Chinese, subjects with rs10420321 GG and rs8111085 CC genotype of the DNMT1 gene were associated with reduced risks for H.pylori infection and higher risks for GA, supporting the hypothesis that polymorphisms of DNMTs may influence the enzyme activities to affect the H.pylori infection and carcinogenesis (Jiang et al, 2012). DNA methyltransferase-3a (DNMT3a) also plays a significant part in the development of embryogenesis and in the generation of aberrant methylation in carcinogenesis.…”

Helicobacter pylori and Gastric Cancer

“…Among these are cytokine genes involved in the adaptive immune system [98,99,100] and pattern recognition factors initiating the innate immune system [101,102]. Furthermore, variation of genes encoding for proteases [103], xenobiotic metabolism enzymes [104], cell cycle regulators [105,106], mucins [107], HLA molecules [108], transcription factors [109], DNA repair enzymes [105,110,111], and micro-RNAs [112] has been reported to bear an increased risk for gastric cancer. Besides a ‘single gene' approach, also pathway-related pattern searches can be performed to allow a broader assessment of the pathobiological background [113].…”

DNMT1 , DNMT3A and DNMT3B Polymorphisms Associated With Gastric Cancer Risk: A Systematic Review and Meta-analysis

“…It is catalyzed by a family of DNA methyltransferases (DNMTs) mainly consisting of three activated forms: DNMT1, DNMT3A and DNMT3B. DNMT1 is thought to be a maintenance DNA methyltransferase which principally maintains CpG methylation, involving in embryonic development and somatic cells survival (Brown and Robertson, 2007) and it is encoded by DNMT1 gene which locates on chromosome 19p13.2 (Jiang et al, 2012a). DNMT3A and DNMT3B are considered as de novo methyltransferases which are required for the establishment of embryonic methylation patterns, mainly occurring during gametogenesis and early development (Okano et al, 1999) and they are encoded by DNMT3A and DNMT3B genes locating on chromosome 2p23 and 20q11.2 respectively (Yang et al, 2012).…”

“…However, the associations between DNMTs SNPs and GC risk were still conflicting (Jiang et al, 2012a, Yang et al, 2012). Therefore, for the first time, the effects of DNMTs polymorphisms on the susceptibility to GC were systematically and comprehensively estimated.…”